HIV-1 subtype B determinants of neuropathogenesis: Viral characteristics associated with dementia

Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is a severe neurological disease resulting from HIV-1 infection of cells in the central nervous system (CNS). Significant genetic compartmentalization has been detected between virus in the periphery and virus in the cerebrospinal fluid (CSF)/CNS in subjects with dementia. Although progress has been made over the past thirty years in understanding HIV-1-associated dementia, the mechanisms leading to the development of neurological disease during HIV-1 infection remain unclear. In this dissertation, I examine the neuropathogenesis of HIV-1 over the course of infection by determining the viral characteristics associated with the development of dementia in HIV-1-infected adults. Compartmentalization between the periphery and the CNS has not been previously described for subjects with primary HIV-1 infection. I detected compartmentalized HIV-1 variants in the CSF of a subset of primary infection subjects, and using longitudinal analyses I found that compartmentalization in the CSF can be resolved during primary infection.;Compartmentalized HIV-1 variants in the CNS/CSF of subjects with dementia are thought to replicate in long-lived perivascular macrophages and/or microglia in the CNS. I examined the source of compartmentalized HIV-1 in the CSF of subjects with neurological disease and in neurologically-asymptomatic subjects who were initiating antiretroviral therapy. In subjects with neurological disease, I found that rapid decay of CSF-compartmentalized variants was associated with high CSF pleocytosis, whereas slow decay measured for CSF-compartmentalized variants in subjects with neurological disease was correlated with low peripheral CD4 cell count and reduced CSF pleocytosis. The longer half-lives I detected suggest that compartmentalized HIV-1 in the CSF of some HAD subjects may be originating from a long-lived cell type in the brain. I also examined the viral genotypes and phenotypes associated with the CSF-compartmentalized variants with differential decay rates. I detected significant compartmentalization in the CSF HIV-1 population for subjects with neurological disease, and the envelope phenotype characterization revealed two distinct classes of viral encephalitis associated with extensive genetic compartmentalization and the clinical diagnosis of dementia. These results will form the basis of future studies to decipher the biology underlying viral evolution and enhanced HIV-1 replication in the CNS.